Injured and diseased tissues or organs have traditionally been treated or replaced by autologous grafts, allogenic grafts, or synthetic or natural-based biomaterials. However, there is a huge global shortage of tissue grafts. Donor tissue grafts may also cause donor site morbidity and loss of organ functionality and allogenic grafts are associated with the risk of disease transmission and often require the use of immunosuppressant drugs. As for synthetic biomaterials, although many of them have achieved widespread clinical use, seamless integration and immunological response issues still remain. These issues have led to the more recent paradigm shift to the development of tissue-engineered biomaterials and devices that mimic the extracellular matrix (ECM) of the natural tissue for tissue engineering. For these biomaterials to be successful, they need to be mechanically robust and elastic to support and maintain tissue structure, and cell friendly and bio-interactive to allow seamless host-biomaterial integration that helps restore tissue functionality.
The collagens are a family of ECM macromolecules within the body that contribute to both mechanical properties and biological function of various types of tissues such as cornea, skin, bone, tendons, ligaments, blood vessels, and the heart. Although very robust in vivo, extracted collagen is rapidly degraded and lacks the mechanical toughness and elasticity, due to the dissociation of natural cross-links during isolation and purification process.
Present chemical crosslinking techniques often result in collagen-based scaffolds that are either too soft or too brittle, that are not robust enough to resist surgical manipulations or do not actively interact with the body cells and tissues. There is, hence, a need for improved collagen scaffolds that are implantable for tissue engineering and regenerative medicine applications.
In the area of corneal transplant there is an unmet need for an alternative to donor corneas. Prosthetic artificial corneas, cell-based therapies, and scaffold-based therapies have been rigorously pursued but their clinical use has been limited due to challenges including: lack of integration into the surrounding tissue; limited cell sources and functionality; inefficient interaction with host cells and incapability of delivery of therapeutic drugs, respectively. Transplantation of cell-free collagen-based into animal and diseased human corneas have been reported. These scaffolds replace the extracellular matrix or stroma, allowing host cells and nerves to eventually grow over and around the scaffold. However, in blinding conditions of the cornea, such as limbal epithelial stem cell deficiency (LSCD, burn-induced wounds or infection leading to inflammation and neovascularization, use of a stromal scaffold alone (human or tissue-engineered) is insufficient—the underlying stem cell deficiency, inflammation and/or neovascularization must also be addressed to avoid eventual graft failure. For patients with LSCD, transplantation of limbal grafts or ex vivo expanded limbal epithelial stem cells is first required. After limbal restoration, central transplantation (keratoplasty) follows to treat scarring in the visual axis. When corneal scarring is complicated with corneal neovascularization and/or severe infections such as herpes simplex keratitis (HSK), anti-inflammatory, anti-angiogenic, antimicrobial or antiviral agents are administered in conjunction with the standard corticosteroid treatment following (or prior to) the high-risk keratoplasties. These therapeutic regimens are most commonly administered topically with the main challenge of low drug penetration through the corneal epithelium. Limited diffusion across the cornea and the increased washing through the tear drainage result in a low bioavailability of 1-7% for most approved drugs. New administration routes, and ideally a controlled-release drug and cell delivery through biodegradable polymeric implants, would lead to increased success rates of corneal transplantation in these severe inflamed corneas.
In these high-risk applications, bioengineered implants are required not only as transparent and robust scaffolds to replace diseased corneal tissue, but also to deliver therapeutics or stem cells into the cornea. These requirements could be opposing—release of cells or substances requires a degree of bio-degradation, however, this could compromise optical transparency and corneal integrity. Also, requirements of transparency and non-toxicity of biomaterials may complicate the ability to encapsulate, deliver and monitor cells and therapeutic substance release in vivo.